Despite scattered studies that have reported mutations in the
tet(A) gene potentially linked to tigecycline resistance in clinical pathogens, the detailed function and epidemiology of these
tet(A) variants remains limited. In this study, we analyzed 64
Escherichia coli isolates derived from MacConkey plates supplemented with tigecycline (2 μg/mL) and identified five distinct
tet(A) variants that account for reduced sensitivity to tigecycline. In contrast to varied tigecycline MICs (0.25 to 16 μg/mL) of the 64
tet(A)-variant-positive
E. coli isolates, gene function analysis confirmed that the five
tet(A) variants exhibited a similar capacity to reduce tigecycline sensitivity in DH5α carrying pUC19. Among the observed seven non-synonymous mutations, the V55M mutation was unequivocally validated for its positive role in conferring tigecycline resistance. Interestingly, the variability in tigecycline MICs among the
E. coli strains did not correlate with
tet(A) gene expression. Instead, a statistically significant reduction in intracellular tigecycline concentrations was noted in strains displaying higher MICs. Genomic analysis of 30 representative
E. coli isolates revealed that
tet(A) variants predominantly resided on plasmids (
n = 14) and circular intermediates (
n = 13). Within China, analysis of a well-characterized
E. coli collection isolated from pigs and chickens in 2018 revealed the presence of eight
tet(A) variants in 103 (4.2%, 95% CI: 3.4–5.0%) isolates across 13 out of 17 tested Chinese provinces or municipalities. Globally, BLASTN analysis identified 21
tet(A) variants in approximately 20.19% (49,423/244,764) of
E. coli genomes in the Pathogen Detection database. These mutant
tet(A) genes have been widely disseminated among
E. coli isolates from humans, food animals, and the environment sectors, exhibiting a growing trend in
tet(A) variants over five decades. Our findings underscore the urgency of addressing tigecycline resistance and the underestimated role of
tet(A) mutations in this context.
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